Oxa-and thia-diazole muscarinic receptor antagonists

ABSTRACT

A compound of formula (I) ##STR1## wherein R 1  is C 1-6  alkyl, halo-(C 1-6  alkyl), C 3-7  cycloalkyl, C 2-6  alkylnyl, hydroxy-(C 2-6  alkylnyl), (C 1-4  alkoxy)-(C 2-6  alkylnyl), aryl, aryl-(C 1-4  alkyl), heteroaryl or heteroaryl-(C 1-4  alkyl); R 2  is H or C 1-4  alkyl; R 3  is aryl, heteroaryl, 2,3-dihydrobenzofuranyl or C 4-7  cycloalkyl; X is O or S; Y is bond, --CH 2  --, --(CH 2 ) 2  -- or --CH 2  O--, a pharmaceutically acceptable salt thereof, which are useful muscarinic receptor antagonists in treaatment of e.g. irritable bowel syndrome, urinary incontinence, etc.

This application is a 371 of PCT/EP97/00525 filed Feb. 4, 1997.

This invention relates to substituted oxadiazole and thiadiazolederivatives. The compounds of the invention are muscarinic receptorantagonists which are selective for smooth muscle muscarinic sites overcardiac muscarinic sites and which do not have any significantantihistaminic activity. Thus the compounds are useful in the treatmentof diseases associated with altered motility and/or tone of smoothmuscle which can, for example, be found in the gut, trachea and bladder.Such diseases include irritable bowel syndrome, diverticular disease,urinary incontinence, oesophageal achalasia and chronic obstructiveairways disease.

The compounds are also useful as cognition enhancers, and are thususeful in treating diseases involving memory impairment such asAlzheimer's disease and age-related memory disorder.

According to the invention there are provided compounds of the formula:##STR2## wherein R¹ is C₁ -C₆ alkyl, halo-(C₁ -C₆ alkyl), C₃ -C₇cycloalkyl, C₂ -C₆ alkynyl, hydroxy-(C₂ -C₆ alkynyl), (C₁ -C₄alkoxy)-(C₂ -C₆ alkynyl), aryl, aryl-(C₁ -C₄ alkyl), heteroaryl orheteroaryl-(C₁ -C₄ alkyl);

R² is H or C₁ -C₄ alkyl;

R³ is aryl, heteroaryl, 2,3-dihydrobenzofuranyl or C₄ -C₇ cycloalkyl;

X is O or S;

and Y is a direct link, --CH₂ --, --(CH₂)₂ -- or --CH₂ O--;

and their pharmaceutically acceptable salts.

By halo is meant chloro, bromo, fluoro or iodo.

Preferred aryl groups are phenyl and naphthyl both optionallysubstituted by up to 3 substituents each independently selected from C₁-C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, halo and trifluoromethyl.

More preferably, the aryl groups are selected from phenyl optionallysubstituted by 1 or 2 substituents each independently selected from C₁-C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, halo and trifluoromethyl; andnaphthyl.

Most preferably, the aryl group is phenyl, fluorophenyl, dichlorophenyl,hydroxyphenyl, methoxyphenyl or naphthyl.

Preferred heteroaryl groups are thienyl, pyridyl, thiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl and pyrimidinyl, all optionallysubstituted by 1 or 2 substituents each independently selected from C₁-C₄ alkyl, C₁ -C₄ alkoxy, hydroxy and halo.

More preferred heteroaryl groups are thienyl, pyridyl, thiazolyl andbenzothiazolyl.

Preferred alkyl groups are methyl and ethyl. Preferred alkoxy groups aremethoxy and ethoxy. Preferred halo groups are chloro, bromo and fluoro.Preferred cycloalkyl groups are cyclobutyl, cyclopentyl and cyclohexyl,particularly cyclobutyl. The preferred alkynyl group is ethynyl.Preferred hydroxy-(C₂ -C₆ alkynyl) groups are HO--CH₂ C.tbd.C-- andHO--(CH₂)₄ --C.tbd.C--. The preferred haloalkyl groups aretrifluoromethyl and pentafluoroethyl.

R¹ is preferably C₁ -C₆ alkyl; pentafluoroethyl; C₄ -C₆ cycloalkyl;ethynyl; --C--C--CH₂ OH; --C.tbd.C--(CH₂)₄ OH; a phenyl group optionallysubstituted by 1 or 2 substituents each independently selected fromhalo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and hydroxy; naphthyl; or aheterocyclic group selected from thienyl, pyridyl, thiazolyl andbenzothiazolyl, all optionally substituted by halo, C₁ -C₄ alkyl, C₁ -C₄alkoxy or hydroxy.

R² is preferably H or CH₃.

R³ is preferably either phenyl optionally substituted by 1 or 2substituents each independently selected from halo, C₁ -C₄ alkyl, C₁ -C₄alkoxy and hydroxy; 2,3-dihydrobenzofuranyl; C₄ -C₇ cycloalkyl orthienyl.

X is preferably O.

Y is preferably a direct link, --CH₂ -- or --CH₂ O--.

The pharmaceutically acceptable salts of the compound of formula (I)include acid addition salts such as the hydrochloride, hydrobromide,hydrofluoride. sulphate or bisulphate, phosphate or hydrogen phosphate,acetate, besylate, citrate, fumarate, gluconate, lactate, maleate,mesylate, succinate and tartrate salts. For a more comprehensive list ofpharmaceutically acceptable salts see, for example, the Journal ofPharmaceutical Sciences, Vol. 66, No. 1, January 1977, pages 1-19. Thesesalts can be prepared conventionally, e.g. by mixing a solution of thefree base and the acid in a suitable solvent, e.g. ethanol, andrecovering the acid addition salt either as a precipitate, or byevaporation of the solution.

The compounds (I) may contain one or more optically active centres andthe invention includes both the separated and unseparated forms. Theseparated forms can be obtained by conventional means, e.g. by usinghigh performance liquid chromatography employing a chiral stationaryphase, or by chemical resolution via the formation of suitable salts orderivatives.

One method to the compounds (I) is via the ketones (II): ##STR3## whereX, Y, R² and R³ are as defined for formula (I), by reaction with aGrignard, organolithium or organocerium reagent of the formula:

R¹ MgHal, R¹ Li or R¹ CeCl₂

where Hal is Cl or Br, in a suitable organic solvent.

When an organolithium or organocerium reagent is used, the reaction istypically carried out at low temperature, i.e. at 0° C. or below, andpreferably at about -78° C.

A preferred organic solvent is tetrahydrofuran.

The preferred Grignard reagents are the magnesium bromides.

The Grignard reagents can be generated in situ, e.g. by adding a halideof the formula R¹ Hal dropwise to a suspension of magnesium turnings inan organic solvent such as diethyl ether at a rate sufficient tomaintain reflux. After stirring for, say, about 30 minutes at roomtemperature, the resulting solution containing the Grignard reagent isadded dropwise to a solution of the ketone (II) in a suitable organicsolvent, typically at a temperature of 0° to -20° C.

The product can be isolated from the reaction mixture conventionally.

The novel intermediates (II) also form a part of the invention.

The intermediates (II) in which X is O are preparable by conventionaltechniques, e.g. as follows: ##STR4## An alternative route to theintermediates (IIA) is as follows: ##STR5## Routes to the thiadiazoleintermediates are as follows: ##STR6## Another method to the compounds(I) is from a hydroxy-containing compound (III) or base salt thereof:##STR7## wherein R¹ and X are as defined for formula (I), either (a) byreaction with a compound of the formula (IV):

    Q--CH(R.sup.2)--Y--R.sup.3                                 (IV)

wherein Q is a leaving group such as tosyloxy, mesyloxy,trifluoromethanesulfonyloxy, Cl or Br and R², R³ and Y are as definedfor formula (I); or (b), by reaction with an aldehyde or ketone of theformula ##STR8## wherein R², R³ and Y are as defined for formula (I), inthe presence of a reducing agent, e.g. sodium triacetoxyborohydride orsodium cyanoborohydride, in a suitable organic solvent, e.g.tetrahydrofuran, and typically at room temperature.

When the free base of compound (III) is used in (a), the reaction istypically carried out in the presence of an acid acceptor such as sodiumbicarbonate or ethyidiisopropylamine.

The compounds of the formula (III) can be prepared by removal of thebenzyl group from the compounds of the formula (I) in which the group"--CH(R²)--Y--R³ " is benzyl, typically by reaction with a suitablechloroformate, e.g. α-chloroethylchloroformate, in a suitable organicsolvent, e.g. dichloromethane or toluene, and preferably under reflux.

The selectivity of the compounds (I) as muscarinic receptor antagonistscan be measured as follows.

Male guinea pigs are sacrificed and the ileum, trachea, bladder andright atrium are removed and suspended in physiological salt solutionunder a resting tension of 1 g at 32° C. aerated with 95% O₂ and 5% CO₂.Contractions of the ileum, bladder and trachea are recorded using anisotonic (ileum) or isometric transducer (bladder and trachea). Thefrequency of contraction of the spontaneously beating right atrium isderived from isometrically recorded contractions.

Dose-response curves to either acetylcholine (ileum) or carbachol(trachea, bladder and right atrium) are determined using a 1-5 minutecontact time for each dose of agonist until the maximum response isachieved. The organ bath is drained and refilled with physiological saltsolution containing the lowest dose of the test compound. The testcompound is allowed to equilibrate with the tissue for 20 minutes andthe agonist dose-response curve is repeated until the maximum responseis obtained. The organ bath is drained and refilled with physiologicalsalt solution containing the second concentration of test compound andthe above procedure is repealed. Typically four concentrations of thetest compound are evaluated on each tissue.

The concentration of the test compound which Causes a doubling of theagonist concentration to produce the original response is determined(pA₂ value--Arunlakshana and Schild (959), Brit. J. Pharmacol., 14,48-58). Using the above analytical techniques, tissue selectivity formuscarinic receptor antagonists is determined.

Activity against agonist induced broncho-constriction or gut or bladdercontractility in comparison with chances in heart rate is determined inthe anaesthetised dog. Oral activity is assessed in the conscious dogdetermining compound effects on, for example, heart rate, pupil diameterand cut motility.

Compound affinity for other cholinergic sites is assessed in the mouseafter either intravenous or intraperitoneal administration. Thus, thedose which causes a doubling of pupil size is determined as well as thedose which inhibits the salivation and tremor responses to intravenousoxotremorine by 50%.

For administration to man in the curative or prophylactic treatment ofdiseases associated with the altered motility and/or tone of smoothmuscle, such as irritable bowel syndrome, diverticular disease, urinaryincontinence, oesophageal achalasia and chronic obstructive airwaysdisease, oral dosages of the compounds will generally be in the range offrom 3.5 to 350 mg daily for an average adult patient (70 kg). Thus fora typical adult patient, individual tablets or capsules will typicallycontain from 1 to 250 mg of active compound, in a suitablepharmaceutically acceptable vehicle or carrier for administration singlyor in multiple doses, once or several times a day. Dosages forintravenous administration will typically be within the range 0.35% to35 mg per single dose as required. In practice the physician willdetermine the actual dosage which will be most suitable for anindividual patient and it will vary with the age, weight and response ofthe particular patient. The above dosages are exemplary of the averagecase but there can, of course, be individual instances where higher orlower dosage ranges are merited, and such are within the scope of thisinvention.

For human use, the compound of the formula (I) can be administeredalone, but will generally be administered in admixture with apharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. For example, theycan be administered orally in the form of tablets containing suchexcipients as starch or lactose, or in capsules or ovules either aloneor in admixture with excipients, or in the form of elixirs orsuspensions containing flavouring or colouring agents. They can beinjected parenterally, for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances,for example, enough salts or glucose to make the solution isotonic withblood.

In a further aspect the invention provides a pharmaceutical compositioncomprising a compound of the formula (I), or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablediluent or carrier.

The invention also includes a compound of the formula (I) or apharmaceutically acceptable salt thereof, for use as a medicament,particularly for use in the treatment of urinary incontinence orirritable bowel syndrome.

The invention further includes the use of a compound of the formula (I),or of a pharmaceutically acceptable salt thereof, for the manufacture ofa medicament for the treatment of diseases associated with the alteredmotility and/or tone of smooth muscle, such as irritable bowel syndrome,diverticular disease, urinary incontinence, oesophageal achalasia andchronic obstructive airways disease.

The invention yet further includes any novel intermediates describedherein.

The synthesis of the compounds of the formula (I), and of certainintermediates for use therein, are illustrated by the following Examplesand Preparations, respectively.

The purity of compounds was routinely monitored by thin layerchromatography using Merck Kieselgel 60 F₂₅₄ plates. ¹ H Nuclearmagnetic resonance (nmr) spectra were recorded using Bruker AC-300 andVarian Unity 300 spectrometers and were in all cases consistent with theproposed structures. Chemical shifts are given in parts per million (δ)downfield from tetramethylsilane using standard conventionalabbreviations for the designation of major peaks, e.g singlet (s),doublet (d), doublet of doublets (dd), triplet (t), quartet (q),multiplet (m), and broad (b). LRMS means low resolution mass spectrum.Room temperature is 20-25° C.

PREPARATION 1 1-Acetylpiperidine-4-carboxylic acid ##STR9##

Piperidine-4-carboxylic acid (208 g, 1.63 moles) was dissolved in aceticanhydride and the resulting solution heated at reflux under a nitrogenatmosphere for 48 hours. The flask contents were allowed to cool thenconcentrated under reduced pressure to give a pale yellow oil whichsolidified on standing. Recrystallisation from propan-2-ol then affordedthe title compound as an off white solid (160 g, 0.94 moles, 58%), mp164-166° C. (IPA-ethylacetate), δ_(H) (300 MHz;CDCl₃) 1.7 (2H, m), 2.0(2H, m), 2.2 (3H, s), 2.6 (1H, m), 2.85 (1H, m), 3.2 (1H, m), 3.8 (1H,m), and 4.4 (1H, m).

PREPARATION 2 1-Acetylpiperidine-4-(2-oxo-2-phenylethyl)carboxamide##STR10##

Carbonyidiimidazole (CDI) (212.0 g, 1.31 moles) was added portionwise toa stirred suspension of 1-acetylpiperidine-4-carboxylic acid (200.0 g,1.17 moles) in dry dichloromethane under nitrogen at room temperature[care CO₂ evolution]. The resulting solution was then stirred at roomtemperature under nitrogen for 2 hours. α-Aminoacetophenonehydrochloride (210 g, 1.22 moles) was added followed by triethylamine(170 cm³, 1.22 moles) causing a slight exotherm. The resulting mixturewas stirred at ambient temperature under nitrogen overnight. The flaskcontents were then washed with aqueous hydrochloric acid (2l, 2M) anddeionised water (2×1 l), dried over anhydrous sodium sulphate andconcentrated under reduced pressure to give the title compound as anorange solid (300 g, 1.04 moles, 79%), Rf 0.15 (95:5 CH₂ Cl₂ :MeOH), mp161-162° C., δ_(H) (300 MHz;CDCl₃) 1.7 (2H, m), 1.9 (2H, m), 2.1 (3H,s), 2.5 (1H, m), 2.7 (1H, t), 3.1 (1H, t), 3.9 (1H, d), 4.6 (1H, d), 4.8(2H, d), 6.6 (1H, s), 7.5 (2H, m), 7.6 (1H, m), and 7.9 (2H, d).

PREPARATION 3 3-Benzoyl-5-{4-(1-acetylpiperidinyl)}-1,2,4-oxadiazole##STR11##

1-Acetylpiperidine-4-(2-oxo-2-phenylethyl)carboxamide (294 g, 1.02moles) was dissolved in glacial acetic acid (1.5 l) with gentle warming.A solution of sodium nitrite (100 g) in deionised water (120 cm³) wasthen added dropwise over a period of 2 hours with slight cooling from anice-water bath. The resulting reaction mixture was stirred at ambienttemperature for 144 hours adding further sodium nitrite (100 g) indeionised water (120 cm³) every 48 hours. The flask contents were thenpurged with nitrogen and concentrated under reduced pressure to give asolid residue which was dissolved in dichloromethane (2.5 l) and washedsuccessively with deionised water (500 cm³), aqueous sodium hydroxide(200 cm³, 10% w/v), and deionised water (500 cm³). The resulting organicfraction was dried over anhydrous sodium sulphate and concentrated underreduced pressure to give the title compound as a pale yellow solid, (231g, 0.77 moles, 77%), Rf 0.26 (95:5 CH₂ Cl₂ :MeOH), mp 97-100° C. δ_(H)(300 MHz;CDCl₃) 1.9 (2H, m), 2.1 (3H, s), 2.2 (2H, m), 2.9 (1H, t), 3.3(2H, m), 3.9 (1H, d), 4.5 (1H, d), 7.5 (2H, t), 7.6 (1H, t), and 8.2(2H, d); m/z (LRMS) 322 (MNa⁺), 317 (MNH₄ ⁺), and 300 (MH⁺).

PREPARATION 4 3-Benzoyl-5-(4-piperidinyl)-1,2,4-oxadiazole hydrochloride##STR12##

3-Benzoyl-5-{4-(1-acetylpiperidinyl)}-1,2,4-oxadiazole (230 g, 0.77moles) was dissolved in HCl saturated methanol (2.5 l) and heated atreflux for 24 hours. The flask contents were then allowed to cool andconcentrated hydrochloric acid (10 cm³) was added. The reaction mixturewas then heated at reflux for a further 20 hours after which tic showedno starting material remaining. The flask contents were then cooled inan ice-acetone bath producing a white solid which was filtered andwashed with ethyl acetate to afford the title compound (175 g, 0.58moles, 75%), mp 224-227° C., δ_(H) (300 MHz;CDCl₃) 2.1 (2H, m), 2.3 (2H,m), 3.1 (2H, m), 3.3 (2H, m), 3.6 (1H, m), 7.6 (2H, m), 7.8 (1H, m), and9.1 (1H, s); m/z (LRMS) 258 (MH⁺).

PREPARATION 5 3-Benzoyl-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole##STR13##

Benzyl bromide (67 cm³, 0.56 moles) was added to a mixture of3-benzoyl-5-(4-piperidinyl)-1,2,4-oxadiazole hydrochloride (165 g, 0.56moles) and solid potassium carbonate (194 g, 1.40 moles) in butan-2-one(1.6 l). The flask contents were then stirred at ambient temperatureunder nitrogen for 48 hours. Deionised water (1.3 l) was then added andthe mixture stirred vigorously for 1 hour. The organic layer wascollected and the remaining aqueous fraction extracted with ethylacetate (500 cm³).

The combined organic fractions were then dried over anhydrous sodiumsulphate and concentrated to give a pale yellow oil. Flashchromatography (1 kg "Kieselgel 60"™ silica) eluting with 8% methanol indichloromethane gave a colourless oil which was azeotroped with tolueneto afford the title compound as a white solid (177 g, 0.51 moles, 91%),Rf 0.6 (95:5 CH₂ Cl₂ :MeOH), mp 67-69° C., δ_(H) (300 MHz;CDCl₃) 2.1(6H, m), 2.9 (2H, d), 3.1 (1H, m), 3.6 (2H, s), 7.3 (5H, m), 7.5 (2H,t), 7.7 (1H, t), and 8.3 (2H, d); m/z (LRMS) 348 (MH⁺).

PREPARATION 6 2-tert-Butyldimethylsiloxyphenylacetonitrile ##STR14##

Mandelonitrile (50 g, 0.38 moles) and imidazole (64 g, 0.94 moles) weredissolved in DMF (100 cm³) and the resulting solution cooled in anice-water bath. tert-Butyldimethylsilyl chloride (68 g, 0.45 moles) wasthen added portionwise over a period of 20 minutes. The flask contentswere then warmed to 35° C. and stirred at that temperature for 18 hours.The reaction mixture was then cooled and partitioned between ethylacetate (3×100 cm³) and deionised water (100 cm³). The combined organicfractions were then washed with brine (100 cm³), dried over anhydrousmagnesium sulphate and concentrated under reduced pressure to give thecrude product as a yellow oil. Flash chromatography (600 g kieselgel 60silica) eluting with 20% dichloromethane in pentane gave the titlecompound as an oil (77 g, 0.31 moles, 82%), δ_(H) (300 MHz;CDCl₃) 0.1(3H, s), 0.2 (3H, s), 1.0 (9H, s), 5.5 (1H, s), and 7.4 (5H, m).

PREPARATION 7 α-tert-Butyldimethylsiloxybenzylamidoxime ##STR15##

Solid potassium carbonate (54 g, 0.39 moles) was added to a mixture of2-tert-butyldimethylsiloxyphenylacetonitrile (45 g, 018 moles) andhydroxylamine hydrochloride (25 g, 0.36 moles) in ethanol (450 cm³) andthe resulting mixture heated at reflux under nitrogen for 2 hours. Theflask contents were then cooled and concentrated under reduced pressure.The resulting residue was partitioned between dichloromethane (3×150cm³) and deionised water (100 cm³). The combined organic fractions werethen washed with brine (100 cm³), dried over anhydrous magnesiumsulphate and concentrated under reduced pressure to give the titlecompound as a yellow solid(53.2 g, 0.18 motes, 100%). δ_(H) (300MHz;CDCl₃) 0.1 (3H, s), 0.2 (3H, s), 1.0 (9H, s), 4.8 (2H, bs), 5.3(1H,bs), 7.3 (3H, m), and 7.5 (2H, m).

PREPARATION 83-(α-tert-Butyldimethylsiloxybenzyl)-5-{4-(1-benzylpiperidinyl)}1,2,4-oxadiazole##STR16##

α-tert-Butyldimethylsiloxybenzylamidoxime (53.2 g, 0.18 moles) wasdissolved in THF (400 cm³) and powdered 4 Å sieves (10 g) were added.The resulting mixture was heated at reflux under nitrogen for 15 minutesthen cooled in an ice-bath. Sodium hydride (8.0 g, 60% dispersion, 0.2moles) was added portionwise and the flask contents were allowed to warmto room temperature slowly so as to control effervescence. When hydrogenevolution had ceased, a solution of ethylN-benzylpiperidine-4-carboxylate (45 g, 0.18 moles) in THF (125 cm³) wasadded dropwise. The flask contents were stirred at ambient temperaturefor 30 minutes then heated at reflux under nitrogen for 1.5 hours. Aftercooling the reaction mixture was partitioned between ethyl acetate(2×200 cm³) and deionised water (200 cm³). The combined organicfractions were then washed with brine (100 cm³), dried over anhydrousmagnesium sulphate and concentrated under reduced pressure to give thetitle compound as a tan coloured oil (62 g, 0.13 moles, 72%), δ_(H) (300MHz;CDCl₃) 0.1 (3H, s), 0.2 (3H, s), 1.0 (9H, s), 2.0 (6H, m), 2.9 (3H,m), 3.5 (2H, s), 6.0 (1H, s), 7.3 (8H, m), and 7.5 (2H, m).

PREPARATION 93-(α-hydroxybenzyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole##STR17##

Tetrabutyl ammonium fluoride (237 cm³, 1M in THF) was added dropwise toa stirred solution of3-(α-tert-butyldimethylsiloxybenzyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole(62 g, 0.13 moles) in THF (200 cm³) at 0° C. The resulting mixture wasthen allowed to warm to room temperature and stirred for a further 30minutes. The flask contents were then partitioned between ethyl acetate(3×200 cm³) and deionised water (200 cm³) and the combined organicfractions washed with brine (100 cm³), dried over anhydrous magnesiumsulphate and concentrated under reduced pressure to give the titlecompound as a yellow solid (45.0 g) (Found C, 70.5;H, 6.5; N, 11.8. C₂₁H₂₃ N₃ O₂.1/2H₂ O requires C, 70.4; H, 6.8; N, 11.7%); δ_(H) (300MHz;CDCl₃) 2.0 (6H, m), 2.9 (4H, m), 3.5 (2H, s), 5.9 (1H, d), and 7.3(10H, m); m/z (LRMS) 350 (MH⁺).

PREPARATION 10 3-Benzoyl-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole##STR18##

Manganese dioxide (206 g, 2.37 moles) was added portionwise to amechanically stirred solution of3-(α-hydroxybenzyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole (45.0g, 0.19 moles) in dry THF (300 cm³) at room temperature over a period of2 hours. The resulting mixture was then stirred at room temperature for45 minutes, filtered through an "Arbocel"™ pad, and concentrated underreduced pressure to give a tacky solid. This residue was redissolved ina minimum quantity of hot diisopropyl ether and the resulting solutionwas filtered then cooled in an ice-water bath to give the title compoundas a beige crystalline solid (26 g, 75 mmoles, 58%). This material wasidentical in all respects to that prepared according to Preparation 5.

PREPARATION 113-(1,1-Diphenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole##STR19##

α-Chloroethylchloroformate (0.27 cm³, 2.5 mmoles) was added dropwise toa stirred solution of3-(1,1-diphenyl-1-hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole(1.00 g, 2.30 mmoles) in dry dichloromethane (10 cm³) at 0° C. undernitrogen. The resulting solution was stirred at 0° C. for 40 minutesthen concentrated under reduced pressure. The resulting residue wasdissolved in methanol (20 cm³ ) and heated at reflux for 40 minutes. Theflask contents were then cooled, concentrated under reduced pressure andpartitioned between dichloromethane (100 cm³) and saturated aqueoussodium bicarbonate (50 cm³). The organic fraction was dried overanhydrous sodium sulphate then concentrated under reduced pressure.Flash chromatography (25 g kieselgel 60 silica) eluting with 5 to 15%methanol in dichloromethane gave the title compound as a white foam(0.68 g, 2.0 mmoles, 80%), Rf 0.05 (90:10 CH₂ Cl₂ :MeOH), δ_(H) (300MHz;CDCl₃) 1.9 (2H, m), 2.2 (2H, m), 2.8 (2H, t), 3.1 (1H, m), 3.3 (2H,m), 4.2 (1H, b), and 7.4 (10H, m); m/z (LRMS) 336 (MH⁺).

PREPARATION 123-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole##STR20##

α-Chloroethylchloroformate (3.30 g, 23.0 mmoles) was added dropwise to astirred solution of3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole(8.52 g, 21.0 mmoles) in dry toluene (100 cm³). The resulting mixturewas then heated at reflux under nitrogen for 90 minutes. The flaskcontents were then allowed to cool and the reaction mixture concentratedunder reduced pressure. The resulting residue was dissolved in methanol(50 cm³) and heated at reflux for 40 minutes. The flask contents werethen cooled, concentrated under reduced pressure and partitioned betweendichloromethane (100 cm³) and saturated aqueous sodium bicarbonate (50cm³). The organic fraction was dried over anhydrous sodium sulphate thenconcentrated under reduced pressure. Flash chromatography (25 g"Kieselgel 60" silica) eluting with 5 to 15% methanol in dichloromethanegave the title compound as a white foam (1.63 g, 5.2 mmoles, 23%), δ_(H)(300 MHz:CDCl₃) 1.7 (6H, m), 2.0 (4H, m), 2.7 (4H, m), 3.1 (1H, m), 3.2(2H, m), 3.3 (1H, m), 7.3 (3H, m), and 7.5 (2H, d); m/z (LRMS) 315(MH⁺).

EXAMPLE 13-(1,1-Diphenyl-1-hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole##STR21##

Phenyl lithium (5.0 cm³ ; 1.8M in cyclohexane, 9.0 mmoles) was addeddropwise to a stirred solution of3-benzoyl-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole (3.0 g, 8.6mmoles) in dry tetrahydrofuran (40 cm³) at -78° C. under a nitrogenatmosphere. The resulting solution was allowed to warm to roomtemperature over a period of two hours and was then partitioned betweenethyl acetate (3×50 cm³) and brine (20 cm³). The combined organicfractions were then dried over anhydrous sodium sulphate andconcentrated under reduced pressure. Flash chromatography (30 g"Kieselgel 60" silica) eluting with 35% ethyl acetate in hexane gave thetitle compound (2.9 g, 6.8 mmoles, 76%) Rf 0.8 (ethyl acetate), (FoundC, 75.45;H, 6.4; N, 9.8. C₂₇ H₂₇ N₃ O₂.1/4H₂ O requires C, 75.4; H,6.45; N, 9.8 %); δ_(H) (300 MHz;CDCl₃) 2.0 (6H, m), 2.9 (2H, m), 3.5(2H, s), 3.7 (1H, s), and 7.3 (15H, m); m/z (LRMS) 426 (MH⁺).

EXAMPLE 23-(1-nButyl-1-phenyl-1-hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole##STR22##

The title compound was prepared by a similar method to that described inExample 1 substituting butyl lithium (2.5 M in hexane, 1.1 moleequivalents) in place of phenyl lithium to give the title compound,(Found C, 73.5; H, 7.8; N, 10.0. C₂₅ H₃₁ N₃ O₂ requires C, 74.0; H, 7.7;N, 10.4%); δ_(H) (300 MHz;CDCl₃) 0.8 (3H, m), 1.3 (4H, m), 2.1 (8H, m),2.9 (3H, m), 3.2 (1H, s), 3.5 (2H, m), 7.3 (8H, m), and 7.5 (2H, d); m/z(LRMS) 406 (MH⁺).

EXAMPLE 33-{1-(2-Thienyl)-1-phenyl-1-hydroxymethyl}-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole##STR23##

n-Butyl lithium (1.3 cm³ ; 2.5M in hexane, 3.25 mmoles) was addeddropwise to a stirred solution of thiophene (0.3 cm³, 3.0 mmoles) in drytetrahydrofuran (30 cm³) under nitrogen at -78° C. and the resultingsolution stirred at -78° C. for ten minutes to produce 2-thienyllithium.A solution of 3-benzoyl-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole(1.0 g, 2.9 mmoles) in dry tetrahydrofuran (10 cm³) was then added inone portion and the resulting mixture stirred at -78° C. for one hour.The cooling bath was then removed and the flask contents allowed to warmto room temperature over a period of one hour. The reaction mixture wasthen partitioned between ethyl acetate (3×50 cm³) and brine (20 cm³).The combined organic fractions were then dried over anhydrous sodiumsulphate and concentrated under reduced pressure. Flash chromatography(30 g "Kieselgel 60" silica) eluting with 40% ethyl acetate in hexanethen gave the title compound (0.83 g, 1.9 mmoles, 66%) (Found C. 68.6;H, 5.9; N, 9.5. C₂₅ H₂₅ N₃ O₂ S.1/4H₂ O requires C, 68.9; H, 5.9; N,9.6%); δ_(H) (300 MHz;CDCl₃) 2.1 (6H, m), 2.9 (3H, m), 3.5 (2H, s), 3.95(1H, s), 6.9 (2H, m), 7.3 (9H, m), and 7.5 (2H, m); m/z (LRMS) 432(MH⁺).

EXAMPLES 4-9

The compounds of the following tabulated examples of the general formulashown below were prepared by reaction of3-benzoyl-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole with theappropriate organolithium agent using a similar method to that describedin Example 3.

    __________________________________________________________________________    1  STR24##                                                                         Organo lithium                                                             Example precursor R.sup.1 LRMS Analysis/δ.sub.H (300 MHz;                                                    CDCl.sub.3)                            __________________________________________________________________________      4 2-bromopyridine                                                                                                  2  427 (MH.sup.+) Found C, 72.2;                                              H, 6.2; N, 12.9. C.sub.26 H.sub.26                                            N.sub.4 O.sub.2.1/4H.sub.2 O                                                  requires C, 72.5; H, 6.2; N, 13.0%                                            δ.sub.H (300 MHz; DCl.sub.3)                                            2.0 (6H, m), 2.9 (3H, m), 3.5 (2H,                                            s), 6.65 (1H, s), 7.3 (8H, m),                                                7.45 (3H, m), 7.7 (1H, t), and 8.6                                            (1H, d).                                  - 5 4-bromopyridine                                                                                               3  427 (MH.sup.+) Found C, 73.3;                                              H, 6.1; N, 13.2. C.sub.26 H.sub.26                                            N.sub.4 O.sub.2 requires C, 73.2;                                             H, 6.1; N, 13.1% δ.sub.H                                                (300 MHz; CDCl.sub.3) 2.0 (6H, m),                                            2.9 (3H, m), 3.5 (2H, s), 4.0 (1H,                                            s), 7.3 (12H, m), and 8.5 (2H, d).        - 6 thiazole                                                                                                      4  433 (MH.sup.+) Found C, 66.1;                                              H, 5.5; N, 12.8. C.sub.24 H.sub.24                                            N.sub.4 O.sub.2 S.1/4H.sub.2 O                                                requires C, 66.0; H, 5.65; N,                                                 12.8% δ.sub.H (300 MHz;                                                 CDCl.sub.3) 2.0 (6H, m), 2.9 (3H,                                             m), 3.5 (2H, s), 4.8 (1H, s), 7.3                                             (9H, m), 7.6 (2H, d), and 7.8 (1H,                                            d).                                       - 7 benzothiazole                                                                                                 5  484 (MH.sup.+) Found C, 69.9;                                              H, 5.8; N, 11.1. C.sub.28 H.sub.26                                            N.sub.4 O.sub.2 S requires C,                                                 69.7; H, 5.4; N, 11.6% δ.sub.                                           H (300 MHz; CDCl.sub.3) 2.0 (6H,                                              m), 2.9 (3H, m), 3.5 (2H, s), 5.0                                             (1H, s), 7.3 (10H, m), 7.7 (2H,                                               d), 7.85 (1H, d), and 8.05 (1H,                                               d).                                       - 8 propargyl alcohol                                                                                             6  404 (MH.sup.+) Found C, 69.1;                                              H, 6.2; N, 9.7. C.sub.24 H.sub.25                                             N.sub.3 O.sub.3.3/4H.sub.2 O                                                  requires C, 69.1; H, 6.4; N, 10.1%                                            δ.sub.H (300 MHz; CDCl.sub.3)                                            2.0 (6H, m), 2.9 (3H, m), 3.5                                                (2H, s), 4.4 (2H, s), 7.3 (8H, m),                                            and 7.7 (2H, d).                          - 9 5-hexyne-1-ol                                                                                                 7  446 (MH.sup.+) Found C, 72.1;                                              H, 7.0; N, 9.4. C.sub.27 H.sub.31                                             N.sub.3 O.sub.3.1/4H.sub.2 O                                                  requires C, 72.1; H, 7.05; N, 9.3%                                            δ.sub.H (300 MHz; CDCl.sub.3)                                            1.7 (6H, m), 2.0 (7H, m), 2.4                                                (2H, t), 2.9 (3H, m), 3.5 (2H, s),                                            3.7 (2H, t), 7.3 (8H, m), and 7.7                                             (2H, d).                               __________________________________________________________________________

EXAMPLE 103-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole##STR31##

Cyclobutylbromide (21.7 cm³, 0.23 moles) was added dropwise to asuspension of magnesium turnings (5.7 g, 0.23 moles) in dry diethylether (50 cm³) at such a rate so as to maintain reflux. The resultingmixture was then stirred at room temperature for 30 minutes before beingadded dropwise to a stirred solution of3-benzoyl-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole (40.0 g, 0.115moles) in diethyl ether (400 cm³) and tetrahydrofuran (100 cm³) at -10°C. under a nitrogen atmosphere. The resulting mixture was then allowedto warm to room temperature over a period of 2 hours. The flask contentswere then cooled and saturated aqueous ammonium chloride (30 cm³) addedcautiously. Deionised water (500 cm³) was then added and the mixtureextracted with ethyl acetate (2×200 cm³). The combined organic fractionswere then dried over anhydrous sodium sulphate and concentrated underreduced pressure. Flash chromatography (500 g "Kieselgel 60" silica)eluting with 40-70% ethyl acetate in pentane then gave the titlecompound (31.5 g, 0.78 moles, 68%) (Found C, 73.0; H, 7.4; N, 10.1. C₂₅H₂₉ N₃ O₂.1/4H₂ O requires C, 73.5; H, 7.3; N, 10.3%); δ_(H) (300MHz;CDCl₃) 1.9 (12H, m), 2.9 (3H, m), 3.2 (1H, s), 3.3 (1H, m), 3.5 (2H,s), 7.3 (8H, m), and 7.5 (2H, d); m/z (LRMS) 403 (MH⁺). HPLC ("ChiralpakAD"™ column, 2.5×25 cm) eluting with 20% isopropanol, 0.06%trifluoroacetic acid, 0.03% diethylamine in hexane at 7 cm³ /minute thengave(-)-3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole,[α]^(D) -48°, c 0.1, dichloromethane; and(+)-3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole,[α]_(D) +51°, c 0.1 dichloromethane; (Found C, 74.3: H, 7.2: N, 10.4.C₂₅ H₂₉ N₃ O₂ requires C, 74.4; H 7.2; N, 10.4%).

EXAMPLES 11-15

The compounds of the following tabulated examples of the general formulashown below were prepared by reaction of3-benzoyl-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole with theappropriate Grignard reagent using a similar method to that described inExample 10.

    ______________________________________                                        8  STR32##                                                                                                 Analysis/                                          Example R.sup.1 LRMS δ.sub.H (300 MHz; CDCl.sub.3)                    ______________________________________                                        11     cyclopentyl 418 (MH.sup.+)                                                                          Found C, 74.9; H, 7.7; N,                             10.0. C.sub.26 H.sub.31 N.sub.3 O.sub.2 requires                              C, 74.8; H, 7.5; N, 10.1%                                                     δ.sub.H (300 MHz; CDCl.sub.3) 1.4                                       (2H, m), 1.6 (6H, m), 2.05                                                    (6H, m), 2.9 (4H, m), 3.2                                                     (1H, s), 3.5 (2H, s), 7.3                                                     (8H, m), and 7.6 (2H, d).                                                  12 cyclohexyl 432 (MH.sup.+) Found C, 74.3; H, 7.5; N,                           9.55. C.sub.27 H.sub.33 N.sub.3 O.sub.2. 1/4H.sub.2 O                         requires C, 74.4; H, 7.7; N,                                                  9.6% δ.sub.H (300 MHz;                                                  CDCl.sub.3) 1.05 (3H, m),                                                     1.15 (3H, m), 1.5 (3H, m),                                                    1.7 (2H, m), 2.1 (6H, m),                                                     2.9 (3H, m), 3.2 (1H, s),                                                     3.5 (2H, s), 7.3 (8H, m),                                                     and 7.6 (2H, d).                                                           13 2-naphthyl 475 (MH.sup.+) Found C, 77.7; H, 5.9; N,                           8.8. C.sub.31 H.sub.24 N.sub.3 O.sub.2 requires                               C, 78.3; H, 6.2; N, 8.8%                                                      δ.sub.H (300 MHz; CDCl.sub.3) 2.0                                       (6H, m), 2.9 (3H, m), 3.5                                                     (2H, s), 3.9 (1H, s), 7.3                                                     (8H, m), 7.5 (5H, m), and                                                     7.9 (4H, m).                                                               14 pentafluoroethyl 468 (MH.sup.+) Found C, 59.1; H, 4.7; N,                     9.0. C.sub.23 H.sub.22 N.sub.3 O.sub.2 F.sub.5 requires                       C, 59.1; H, 4.7; N, 8.9%                                                      δ.sub.H (300 MHz; CDCl.sub.3) 2.0                                       (6H, m), 2.9 (3H, m), 3.5                                                     (2H, s), 4.4 (1H, s), 7.3                                                     (5H, m), 7.4 (3H, m), and                                                     7.9 (2H, m).                                                               15 ethynyl 374 (MH.sup.+) Found C, 73.2; H, 6.5; N,                              10.9. C.sub.23 H.sub.23 N.sub.3 O.sub.2.1/20H.sub.2 O                         requires C, 73.3; H, 6.2; N,                                                  11.1% δ.sub.H (300 MHz;                                                 CDCl.sub.3) 2.0 (6H, m),                                                      2.9 (4H, m), 3.5 (2H, s),                                                     3.9 (1H, b), 7.3 (8H, m),                                                     and 7.8 (2H, m).                                                         ______________________________________                                    

EXAMPLE 163-(1,1-Diphenyl-1-hydroxymethyl)-5-[4-{4-fluorophenylmethyl)piperidinyl}]-1,2,4-oxadiazole##STR33##

Solid sodium bicarbonate (0.20 g) was added to a stirred solution of3-(1,1-diphenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole(0.20 g, 0.6 mmoles) and 4-fluoro-phenylmethyl chloride (0.075 cm³, 0.6mmoles) in dry dimethylformamide (1 cm³). The resulting mixture wasstirred under nitrogen at room temperature for 24 hours then partitionedbetween ethyl acetate (3×20 cm³) and saturated aqueous sodium carbonate(20 cm³). The combined organic fractions were then dried over anhydroussodium sulphate and concentrated under reduced pressure. Flashchromatography (40 g "Kieselgel 60" silica) eluting with 30-50% ethylacetate in hexane then gave the title compound (0.07 g, 0.16 mmoles,26%) (Found C, 72.6; H, 5.95; N, 9.4. C₂₇ H₂₆ N₃ O₂ F requires C, 73.1;H, 5.9; N, 9.5%); δ_(H) (300 MHz;CDCl₃) 2.1 (6H, m), 2.9 (3H, m), 3.5(2H, s), 3.75 (1H, s), 6.95 (2H, d), and 7.4 (12H, m); m/z (LRMS) 444(MH⁺).

EXAMPLES 17 AND 18

The compounds of the following tabulated examples of the general formulashown below were prepared by reaction of3-(1,1-diphenyl-l-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole withthe appropriate alkyl halide using a similar method to that described inExample 16.

    __________________________________________________________________________    9  STR34##                                                                    Example                                                                            Alkyl halide      R.sup.4             LRMS  Analysis/δ.sub.H                                                        (300 MHz; CDCl.sub.3)        __________________________________________________________________________      17 3,4-dichlorobenzyl chloride                                                                                               0  494 (MH.sup.+) 496                                                         (MH.sup.+) 498 (M.sup.+)                                                      Found C, 65.5; H, 4.9;                                                        N, 8.6. C.sub.27                                                              H.sub.25 N.sub.3 O.sub.2                                                      Cl.sub.2 requires C,                                                          65.6; H, 5.1; N, 8.7%                                                         δ.sub.H  (300 MHz;                                                      CDCl.sub.3) 2.1 (6H, m),                                                      2.9 (3H, m), 3.5 (2H,                                                         s), 3.75 (1H, s), 7.1                                                         (1H, d), and 7.4 (12H,                                                        m).                             - 18 5-(2-bromoethyl)-2,3-dihydrobenzofuran                                                                                 1  482 (MH.sup.+) Found                                                       C, 74.9; H, 6.5; N, 8.6.                                                      C.sub.30 H.sub.31                                                             N.sub.3 O.sub.3 requires                                                      C, 74.8; H, 6.6; N, 8.7%                                                      δ.sub.H (300 MHz;                                                       CDCl.sub.3) 2.1 (6H, m),                                                      2.5 (2H, m), 2.7 (2H,                                                         m), 3.0 (3H, m), 3.2                                                          (2H, t), 3.9 (1H, s),                                                         4.5 (2H, t), 6.7 (1H,                                                         d), 6.9 (1H, d), 7.0                                                          (1H, s), and 7.4 (10H,                                                        m).                          __________________________________________________________________________

EXAMPLE 193-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-{1-(4-methoxybenzyl)piperidinyl}]-1,2,4-oxadiazole##STR37##

Acetic acid (0.04 g, 0.6 mmoles) was added to a stirred solution of3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole(0.16 g, 0.5 mmoles) in dry tetrahydrofuran (15 cm³) at ambienttemperature under nitrogen. 4-Methoxybenzaldehyde (0.082 g, 0.6 mmoles)and sodium triacetoxyborohydride (0.212 g, 1.0 mmoles) were then addedand the resulting mixture stirred at ambient temperature under nitrogenfor 6 hours. The flask contents were then partitioned betweendichloromethane (100 cm³) and saturated aqueous sodium bicarbonate. Theorganic fraction was collected, dried over anhydrous sodium sulphate,and concentrated under reduced pressure to give a brown oil. Flashchromatography ("Kieselgel 60" silica) eluting with 30-50% ethyl acetatein hexane then gave the title compound (0.125 g, 0.28 mmoles, 56%)(Found C, 71.1; H, 7.25; N, 8.6. C₂₆ H₃₁ N₃ O₃.1/3H₂ O requires C, 71.7;H, 7.2; N, 9.6%); δ_(H) (300 MHz;CDCl₃) 1.6-2.2 (12H, m), 3.2 (1H, s),3.3 (1H, t), 3.4 (2H, s), 3.8 (3H, s), 6.95 (3H, m), 7.3 (4H, m), and7.5 (2H, m); m/z (LRMS) 434 (MH⁺).

EXAMPLES 20 TO 25

The compounds of the following tabulated examples of the general formulashown below were prepared by reaction of3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazolewith the appropriate aldehyde using a similar method to that describedin Example 19.

    __________________________________________________________________________    2  STR38##                                                                    Example                                                                            Aldehyde    R.sup.4             LRMS  Analysis/δ.sub.H (300                                                   MHz; CDCl.sub.3)                   __________________________________________________________________________      20 4-hydroxybenzaldehyde                                                                                               3  420 (MH.sup.+) Found C,                                                    70.1; H, 6.9; N, 9.8. C.sub.25                                                H.sub.29 N.sub.3 O.sub.3.                                                     1/2H.sub.2 O requires C, 70.1;                                                H, 7.1; N, 9.7% δ.sub.H                                                 (300 MHz; CDCl.sub.3) 1.8-2.1                                                 (12H, m), 2.9 (3H, m), 3.1                                                    (1H, s), 3.3 (1H, t), 3.4 (2H,                                                s), 6.7 (2H, d), 7.1 (2H, d),                                                 7.2 (3H, m), and 7.5 (2H, d).                                                   - 21 cyclohexanecarboxalde                                                  hyde                                                                          4  409 (MH.sup.+) Found C,                                                    71.3; H, 8.6; N, 9.8. C.sub.25                                                H.sub.35 N.sub.3 O.sub.2.                                                     3/20CH.sub.2 Cl.sub.2 requires                                                C, 71.5; H, 8.4; N, 9.95%                                                     δ.sub.H (300 MHz;                                                       CDCl.sub.3 ) 0.8 (2H, m), 1.1                                                 (3H, m), 1.4-2.1 (20H, m), 2.9                                                (3H, m), 3.1 (1H, s), 3.3 (1H,                                                t), 7.1 (3H, m), and 7.5 (2H,                                                 d).                                   - 22 thiophene-2- carboxaldehyde                                                                                      5  410 (MH.sup.+) Found C,                                                    67.3; H, 6.7; N, 10.2.                                                        C.sub.23 H.sub.27 N.sub.3                                                     O.sub.2 S. requires C, 67.5;                                                  H, 6.6; N, 10.3% δ.sub.H                                                 (300 MHz; CDCl.sub.3) 1.8-2.1                                                (12H, m), 2.9 (3H, m), 3.1                                                    (1H, s), 3.3 (1H, t), 3.8 (2H,                                                s), 6.9 (2H, m), 7.2 (4H, m),                                                 and 7.5 (2H, d).                      - 23 phenylacetaldehyde                                                                                               6  418 (MH.sup.+) Found C,                                                    74.9; H, 7.5; N, 9.9. C.sub.26                                                H.sub.31 N.sub.3 O.sub.2.                                                     requires C, 74.8; H, 7.4; N,                                                  10.1% δ.sub.H  (300 MHz;                                                CDCl.sub.3) 1.8-2.1 (12H, m),                                                 2.6 (2H, m), 2.8 (2H, m), 2.9                                                 (3H, m), 3.1 (1H, s), 3.3 (1H,                                                t), 7.2 (3H, m), 7.3 (5H, m),                                                 and 7.5 (2H, d).                      - 24 3,4-dichlorobenzaldehyde                                                                                         7  472 (MH.sup.+) Found C,                                                    60.6; H, 5.4; N, 7.2. C.sub.25                                                H.sub.27 N.sub.3 O.sub.2                                                      Cl.sub.2 requires C, 60.3; H,                                                 5.5; N, 8.3% δ.sub.H                                                    (300 MHz; CDCl.sub.3) 1.8-2.1                                                 (12H, m), 2.9 (3H, m), 3.1                                                    (1H, s), 3.3 (1H, t), 3.4 (2H,                                                s), 7.0- 7.6 (8H, m).                 - 25 2,3-dihydrobenzo [b] furan-5-carboxaldehyde                                                                      8  446 (MH.sup.+) Found C,                                                    72.2; H, 7.0; N, 9.0 C.sub.27                                                 H.sub.31 N.sub.3 O.sub.3.                                                     1/4H.sub.2 O requires C, 72.1,                                                H, 7.1, N, 9.4% δ.sub.H                                                 (300 MHz; CDCl.sub.3 ).                                                       1.8-2.1 (10H, m), 2.9 (2H, m),                                                3.1 (2H, m), 3.3 (1H, m), 3.4                                                 (2H, s), 4.5 (2H, t), 6.7 (1H,                                                d), 7.0 (1H, d), 7.2 (1H, s),                                                 7.2 (1H, s) 7.3 (3H, m) and                                                   7.5 (2H, d).                       __________________________________________________________________________

EXAMPLE 263-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-{1-(2-phenoxyethyl)piperidinyl}]-1,2,4-oxadiazole##STR45##

2-Phenoxybromoethane (0.10 g, 0.5 mmoles) was added to a solution of3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole(0.16 g, 0.5 mmoles) in dry tetrahydrofuran (15 cm³) at ambienttemperature under nitrogen. Ethyldiisopropylamine (0.13 g, 1.0 mmoles)was then added and the resulting solution stirred at ambient temperaturefor 7 days. The flask contents were then partitioned between ethylacetate (3×30 cm³) and saturated aqueous sodium bicarbonate solution (10cm³). The combined organic extracts were then dried and concentratedunder reduced pressure. Flash chromatography ("Kieselgel 60" silica)eluting with 3% methanol in dichloromethane then gave the title compound(0.022 g, 0.05 mmoles, 10%) ⁸ H (300 MHz;CDCl ₃) 1.6-2.2 (10H, m), 2.3(2H, t), 2.8 (2H, t), 2.9 (1H, m), 3.0 (2H, m), 3.2 (1H, s), 3.3 (1H,q), 4.1 (2H, t), 6.9 (3H, m), 7.3 (5H, m), and 7.5 (2H, m); m/z (LRMS)434 (MH⁺).

EXAMPLE 273-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-{1-(α-methylbenzyl)piperidinyl}]-1,2,4-oxadiazole##STR46##

The above compound was prepared by reaction of3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazolewith α-methylbenzyl bromide using a method similar to that described forExample 26.

(Found C, 73.8; H, 7.4; N, 9.6. C₂₆ H₃₁ N₃ O₂.1/3H₂ O requires C, 73.8;H, 7.5; N, 9.9 %); δ_(H) (300 MHz;CDCl₃) 1.3 (3H, s), 1.6-2.2 (12H, m),2.8 (2H, m), 3.0 (1H, m), 3.2 (1H, s), 3.3 (1H, t), 3.5 (1H, m), 7.2(8H, m), and 7.5 (2H, m); m/z (LRMS) 419 (MH⁺).

We claim:
 1. A compound of the formula ##STR47## wherein R¹ is C₁ -C₆alkyl, halo-(C₁ -C₆ alkyl), C₃ -C₇ cycloalkyl, C₂ -C₆ alkynyl,hydroxy-(C₂ -C₆ alkynyl), (C₁ -C₄ alkoxy)-(C₂ -C₆ alkynyl), aryl,aryl-(C₁ -C₄ alkyl), heteroaryl or heteroaryl-(C₁ -C₄ alkyl);R² is H orC₁ -C₄ alkyl; R³ is aryl, heteroaryl, 2,3-dihydrobenzofuranyl or C₄ -C₇cycloalkyl; X is O or S; and Y is a direct link, --CH₂ --, --(CH₂)₂ --or --CH₂ O--;or a pharmaceutically acceptable salt thereof.
 2. Acompound as claimed in claim 1 wherein the aryl group is phenyl ornaphthyl both optionally substituted by up to 3 substituents eachindependently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, haloand trifluoromethyl.
 3. A compound as claimed in claim 2 wherein thearyl group is selected from phenyl optionally substituted by 1 or 2substituents each independently selected from C₁ -C₄ alkyl, C₁ -C₄alkoxy, hydroxy, halo and trifluoromethyl; and naphthyl.
 4. A compoundas claimed in claim 3 wherein the aryl group is phenyl, fluorophenyl,dichlorophenyl, hydroxyphenyl, methoxyphenyl or naphthyl.
 5. A compoundas claimed in claim 1 wherein the heteroaryl group is thienyl, pyridyl,thiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl or pyrimidinyl, alloptionally substituted by 1 or 2 substituents each independentlyselected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy and halo.
 6. Acompound as claimed in claim 5 wherein the heteroaryl group is thienyl,pyridyl, thiazolyl or benzothiazolyl.
 7. A compound as claimed in claim1 wherein R¹ is C₁ -C₆ alkyl; pentafluoroethyl; C₄ -C₆ cycloalkyl;ethynyl; --C.tbd.C--CH₂ OH; --C.tbd.C--(CH₂)₄ --OH;a phenyl groupoptionally substituted by 1 or 2 substituents each independentlyselected from halo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and hydroxy; naphthyl;or a heterocyclic group selected from thienyl, pyridyl, thiazolyl andbenzothiazolyl, all optionally substituted by halo, C₁ -C₄ alkyl, C₁ -C₄alkoxy or hydroxy.
 8. A compound as claimed in claim 1 wherein R² is Hor CH₃.
 9. A compound as claimed in claim 1 wherein R³ is phenyloptionally substituted by 1 or 2 substituents each independentlyselected from halo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and hydroxy;2,3-dihydrobenzofuranyl; C₄ -C₇ cycloalkyl or thienyl.
 10. A compound asclaimed in claim 1 wherein X is O.
 11. A compound as claimed in claim 1wherein Y is a direct link, --CH₂ -- or --CH₂ O--. 12.3-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-(1-benzylpiperidinyl)]-1,2,4-oxadiazole;or(+)-3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-(1-benzylpiperidinyl)]-1,2,4-oxadiazole.13. A pharmaceutical composition comprising a compound of the formula(I) or pharmaceutically acceptable salt thereof as claimed in claim 1and a pharmaceutically acceptable diluent or carrier.
 14. A compound ofthe formula (II): ##STR48## where X, Y, R² and R³ are as defined inclaim
 1. 15. A process for preparing a compound of the formula (I) asclaimed in claim 1 or a pharmaceutically acceptable salt thereof, whichcomprises reacting a compound of the formula (II) as claimed in claim 14without a Grignard, organolithium or organocerium reagent of theformula:

    R.sup.1 MgHal, R.sup.1 Li or R.sup.1 CeCl.sub.2

where Hal is Cl or Br and R¹ is as defined in claim 1, in an organicsolvent; said process being followed by, optionally, conversion of theproduct of the formula (I) into a pharmaceutically acceptable salt. 16.A process according to claim 15, wherein a reagent of the formula R¹MgBr or R¹ Li is used, R¹ being as defined in claim
 15. 17. A processfor preparing a compound of the formula (I) as claimed in claim 1, or apharmaceutically acceptable salt thereof, which comprises the reactionof a compound of the formula (III) or base salt thereof: ##STR49##wherein R¹ and X are as defined in claim 1, with either (a) a compoundof the formula (IV):

    Q--CH(R.sup.2)--Y--R.sup.3                                 (IV)

wherein Q is a leaving group and R², R³ and Y are as defined in claim 1;or (b) an aldehyde or ketone of the formula ##STR50## wherein R², R³ andY are as defined in claim 1, in the presence of a reducing agent and inan organic solvent; said process being followed by, optionally,conversion of the product of the formula (I) into a pharmaceuticallyacceptable salt.
 18. A process as claimed in claim 17, wherein theleaving group is tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, Cl orBr, and wherein the reducing agent is sodium triacetoxyborohydride orsodium cyanoborohydride.
 19. A process as claimed in claim 17 whereinwhen the free base of compound (III) is used in (a), and the reaction iscarried out in the presence of an acid acceptor.
 20. A process accordingto claim 19 wherein the acid acceptor is sodium bicarbonate orethyidiisopropylamine.
 21. A process claim according to claim 15 forpreparing the compound3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-(1-benzylpiperidinyl)]-1,2,4-oxadiazole,characterised by reacting cyclobutylmagnesium bromide with3-benzoyl-5-[4-(1-benzylpiperidinyl)]-1,2,4-oxadiazole, followed by, ifdesired, separating said compound into its (+) and (-) enantiomers. 22.A process according to claim 21, characterised in that separation iscarried out by HPLC.
 23. A method of treating irritable bowel syndrome,diverticular disease, urinary incontinence, oesophageal achalasia orchronic obstructive airways disease in a human patient in need of suchtreatment, which comprises administering to said patient a muscarinicreceptor antagonistic effective amount of a compound or pharmaceuticallyacceptable salt thereof as claimed in claim 1.